Patients with Discordant Responses to Antiretroviral Therapy Have Impaired Killing of HIV-Infected T Cells

Abstract

In medicine, understanding the pathophysiologic basis of exceptional circumstances has led to an enhanced understanding of biology. We have studied the circumstance of HIV-infected patients in whom antiretroviral therapy results in immunologic benefit, despite virologic failure. In such patients, two protease mutations, I54V and V82A, occur more frequently. Expressing HIV protease containing these mutations resulted in less cell death, caspase activation, and nuclear fragmentation than wild type (WT) HIV protease or HIV protease containing other mutations. The impaired induction of cell death was also associated with impaired cleavage of procaspase 8, a requisite event for HIV protease mediated cell death. Primary CD4 T cells expressing I54V or V82A protease underwent less cell death than with WT or other mutant proteases. Human T cells infected with HIV containing these mutations underwent less cell death and less Casp8p41 production than WT or HIV containing other protease mutations, despite similar degrees of viral replication. The reductions in cell death occurred both within infected cells, as well as in uninfected bystander cells. These data indicate that single point mutations within HIV protease which are selected in vivo can significantly impact the ability of HIV to kill CD4 T cells, while not impacting viral replication. Therefore, HIV protease regulates both HIV replication as well as HIV induced T cell depletion, the hallmark of HIV pathogenesis.

Author Summary

Although most patients infected with HIV who have persistent viral replication will experience a decline in CD4 T cell number, this is not always the case. In a small subset of patients in whom ART fails to suppress viral replication, CD4 T cell counts do not fall, for unknown reasons. We identified that these patients have an increased frequency of selected protease mutations, which we call discordance associated mutations (DAMs). While wild type protease rapidly induces cell death, protease containing DAMs have an impaired ability to induce cell death, due to a selective defect in cleavage of caspase 8. Furthermore, viruses containing DAMs replicate as efficiently as wild type, yet fail to induce infected cell death. These results demonstrate an unanticipated role of protease in determining the immunologic outcome of HIV infection in vitro and in vivo.